Molecular Alterations in Malignant Pleural Mesothelioma: A Hope for Effective Treatment by Targeting YAP

Abstract

Malignant pleural mesothelioma is a rare and aggressive neoplasm, which has primarily been attributed to the exposure to asbestos fibers (83% of cases); yet, despite a ban of using asbestos in many countries, the incidence of malignant pleural mesothelioma failed to decline worldwide. While little progress has been made in malignant pleural mesothelioma diagnosis, bevacizumab at first, then followed by double immunotherapy (nivolumab plus ipilumumab), were all shown to improve survival in large phase III randomized trials. The morphological analysis of the histological subtyping remains the primary indicator for therapeutic decision making at an advanced disease stage, while a platinum-based chemotherapy regimen combined with pemetrexed, either with or without bevacizumab, is still the main treatment option. Consequently, malignant pleural mesothelioma still represents a significant health concern owing to poor median survival (12-18 months). Given this context, both diagnosis and therapy improvements require better knowledge of the molecular mechanisms underlying malignant pleural mesothelioma's carcinogenesis and progression. Hence, the Hippo pathway in malignant pleural mesothelioma initiation and progression has recently received increasing attention, as the aberrant expression of its core components may be closely related to patient prognosis. The purpose of this review was to provide a critical analysis of our current knowledge on these topics, the main focus being on the available evidence concerning the role of each Hippo pathway's member as a promising biomarker, enabling detection of the disease at earlier stages and thus improving prognosis.

Fig. 1

Cellular processes leading to malignant pleural mesothelioma (MPM) initiation and growth. The asbestos fibers induce MPM by causing chronic inflammation of the parietal pleura recruiting phagocytes [279]. Phagocytes fail to degrade these fibers, which (i) generates reactive oxygen species (ROS) and nitrogen species resulting in a chronic inflammatory reaction, (ii) alters the DNA molecule of the mesothelial cells, with the appearance of chromosomal aberrations and mutations, (iii) impairs DNA repair mechanisms [33, 34], and (iv) leads to epigenetic alterations responsible for uncontrolled growth, resistance to apoptosis, and hence the occurrence of MPM [33, 35, 46, 279]. In addition to their action on the DNA of mesothelial cells, asbestos fibers would activate several signaling pathways (MAPK, PI3K/AKT/mammalian target of rapamycin) involved in the survival of mesothelial cells downstream of tyrosine kinase receptors such as the epidermal growth factor (EGF), hepatocyte growth factor, or downstream integrin receptors. In parallel, signaling from growth factor receptors can be reinforced, these receptors often being overexpressed, thus accentuating the stimulation of the Ras association domain family 1 isoform A (RASSF1A)/Hippo signaling pathway, a pathway involved when it functions physiologically in cellular homeostasis. Malignant pleural mesothelioma are lesions rich in T lymphocytes and fibroblasts, but expression of PDL-1 by tumoral mesothelial cells could inhibit CD4+ and CD8+ T-cell activation or lead to T-cell apoptosis, allowing tumor growing [102]. Finally, the interaction of hyaluronic acid with its main receptor, CD44, regulates matrix assembly, cytoskeleton architecture, cell migration, proliferation and differentiation of cancer stem cells [155, 156], and activates matrix metalloproteinases (MMPs) involved in tumor progression [165]. CD cluster of differentiation, ECM extracellular cell matrix, EGFR EGF receptor, MAPK mitogen activated protein kinase, PD-L1 programmed death-ligand 1, PD1 programmed death-1, PI3K phosphoinositide 3-kinase, STAT Signal Transducers and Activators of Transcription

Fig. 2

Indexed alterations of the expression of members of the RASSF1A/Hippo pathway in malignant pleural mesothelioma (MPM) at a glance. In mammals, the Hippo pathway is subdivided into three groups of proteins: upstream regulators (CD44, NF2, RASSF1A), the core kinases (MST and NDR [nuclear Dbf2-related kinase]) and their respective adapters (not shown) and the end effectors, namely YAP (Yes-associated protein) and its paralogous TAZ (transcriptional co-activator with PDZ-binding motif). CD44, linked to hyaluronic acid (HA), a glycosaminoglycan found abundantly in the pleural cavity leads to cell proliferation/invasion. In healthy mesothelial cells, NF2 negatively regulates the CD44-HA (HA) interaction and thus the pro-tumorigenic activity of CD44 [171], but in MPM, NF2 is inactive in near 50% of MPM [59, 71, 92]. The intracellular segment of CD44 also fixes MST and prevents its action, thus, YAP/TAZ activity cannot be inhibited by their phosphorylation by LATS kinases [172]. Next to this direct inhibition of the activity of Hippo kinases, there are losses of expression of MST1 (MST1 promoter is methylated in 8.5% of MPM cases and leads to worse prognostic of patient [252]) and LATS2 (homozygous deletion mutations are found in 12% of the MPM [250]). Each of these anomalies results in an aberrant activation of YAP, that why, YAP has been shown to be constitutively activated in 59% of patients with MPM [254] while TAZ is reported to be sequestered in cytoplasm from MPM cell lines [252]. CD cluster of differentiation, ECM extracellular cell matrix, EGF epidermal growth factor, EGFR EGF receptor, HGFR hepatocyte growth factor receptor, LATS large tumor suppressor kinase, MST mammalian Ste20-like serine/threonine kinase, NDR nuclear Dbf2-related kinase, TAZ transcriptional co-activator with PDZ-binding motif, YAP Yes-associated protein

Fig. 3

Protein structure of the different members of the Ras association domain family 1 isoform A (RASSF1A)/Hippo pathway. Schematic of the main domains of the members of the RASSF1A/Hippo pathway as the main sites of phosphorylation on tyrosine (Y), serine (S), and threonine (T) regulating their activity (https://www.uniprot.org/uniprot). AIS auto-inhibitory sequence, AS activation segment, ATM ataxia telangiectasia mutant, BD binding domain, CC coiled coil, DAG diacylglycerol, NTR N-terminal regulatory domain, RA Ras association, SARAH SAlvador, RASSF1, Hippo, TAD transactivator domain, TEAD TEA domain family member 1)